Dr Peter Attia Supplements For Longevity Their Efficacy

High-Level Overview

Andrew Huberman sits down with physician Dr. Peter Attia, author of Outlive and host of The Drive, for a deep, skeptical look at one of the most heavily marketed corners of the longevity world: the NAD pathway and supplements such as NR, NMN and NAD infusions. Attia walks through the history of sirtuin research from yeast to mice, the biochemistry of NAD and NADH, the claims around resveratrol, and the handful of human trials on NR and NMN, concluding that the case for these compounds extending lifespan rests on a chain of leaps of faith. Along the way they discuss rapamycin as the most promising geroprotective drug, the Interventions Testing Program, biological age tests, radiation risk, why energy declines with age, and each man's personal supplement routine.

The tone is rigorous but friendly and often funny, with Attia playing the hard-nosed skeptic and Huberman candidly sharing that he takes NMN and NR anyway, along with his theory about workout timing and energy. The conversation moves from a framework for longevity, to detailed mechanism and study-by-study analysis, to practical personal habits, and closes with a blunt reminder that behaviors matter far more than any pill.

The Discussion Explores:

• A framework for longevity: behaviors, disease-specific drugs and geroprotective molecules
• Why rapamycin is the standout geroprotective drug and how Attia uses it
• The sirtuin story, from yeast experiments to one transgenic mouse, and why it is not linked to caloric restriction
• Resveratrol's rise and fall, and the rigor of the Interventions Testing Program
• NAD versus NADH, redox potential, and the leaps of faith behind NAD supplementation
• NR versus NMN versus IV NAD, the human trials, FDA status and the one intriguing skin cancer signal
• Biological age tests, radiation fears and why the 50s to 70s are the critical decades
• Both hosts' supplement regimens and the Titanic analogy for putting supplements in perspective

Deep Dive into Main Ideas

A Framework for Thinking About Longevity

Huberman proposes four categories of longevity approaches: the basic do's and don'ts, interventions that reduce calories, glucose, insulin and mTOR signaling, targeting specific cellular pathways like NAD, and the kitchen-sink approach of people like Bryan Johnson. Attia prefers a mutually exclusive framing. First come the unavoidable behaviors, since everyone must eat, sleep and move and can choose to do them well or badly. Second are molecules that target specific diseases. In modern society, he explains, living longer is mathematically equivalent to delaying the onset of chronic disease, namely cardiovascular and cerebrovascular disease, cancer, neurodegenerative disease and metabolic disease, whereas a century ago it meant surviving childbirth, infection and trauma. Third are geroprotective molecules that target hallmarks of aging such as inflammation, senescent cells and impaired nutrient sensing. Fourth is how aggressively you combine them all. He adds that emotional health underpins everything, because without it the hard work of the first category becomes nearly impossible.

Huberman, a developmental neurobiologist, also offers the observation that childhood, with its massive mTOR-driven growth, is actually one of the fastest phases of aging, and Attia confirms it from the yearly birthday photos he takes of his daughter, where the biggest changes happen in the first ten years.

Rapamycin: The Strongest Case

Attia lists the exogenous molecules he takes: disease-specific drugs such as a PCSK9 inhibitor, bempedoic acid and an SGLT2 inhibitor, and rapamycin, taken purely for its potential geroprotection. He takes 8 milligrams once a week, typically two months on and one month off, because of painful mouth ulcers that about 10% of people get, which he jokes is the only biomarker that tells him the drug is working. He says he feels nothing on it. His conviction comes not from mechanism but from experimental data: caloric restriction and rapamycin are the only two interventions ever shown to extend life across yeast, worms, flies and mammals.

He is awaiting results from Matt Kaeberlein's dog aging study, expected in 2026, and another mammalian trial in San Antonio, and says he and some patients helped close a roughly $2.5 million funding gap for the dog study. He also notes that Joan Mannick and Lloyd Klickstein's 2014 study of pulsed everolimus in older adults, which improved vaccine response, turned rapamycin for him from a curiosity into something worth considering, since daily dosing suppresses immunity while weekly pulsing appears to enhance it. Rapamycin, now generic, costs about $5 per milligram, and he notes that because no one profits from it, the research tends to be more honest.

The Sirtuin Story and Caloric Restriction

NAD is present in nearly every cell and serves mainly as a cofactor in 500 to 600 pathways, shuttling electrons back and forth with NADH, and its levels are tightly regulated much like pH. A small fraction is consumed as a substrate by sirtuins during DNA repair, and that is where the longevity story begins. In the late 1990s, Kaeberlein found that overexpressing Sir2 extended lifespan in one yeast strain; soon after, caloric restriction extended life in another strain, leading to the hypothesis that caloric restriction works through sirtuins. Attia explains how this fell apart: each intervention did nothing in the other's strain, and a 2004 study by Kaeberlein and Brian Kennedy in a third strain showed the effects were additive, meaning they are parallel pathways. He says there is no evidence that caloric restriction and sirtuins operate through the same pathway.

As for caloric restriction in humans, he jokes "no one wants to be in the control experiment," nor the treatment group. Severe restriction would likely reduce heart disease, cancer and Alzheimer's risk, but might raise immune problems, sarcopenia and frailty, so it is not clear lifespan improves. In mammals, the only sirtuin result Attia finds convincing is a 2012 transgenic mouse study in which overexpressing SIRT6 extended male lifespan by 10 to 15%, with no effect in females. Sirtuins are thought to improve mitochondrial biogenesis, increase DNA repair and reduce the inflammatory secretions of senescent cells. Huberman explains knockout and transgenic methods, and Attia uses the discovery of Klotho, where knocking a gene out shortened life and overexpressing it extended life by 15 to 20%, as a model of convincing evidence.

Resveratrol and the Gold Standard ITP

Resveratrol, found in trace amounts in grape skins, became famous about 20 years ago as a sirtuin activator. Attia explains that the one positive mouse study used a bizarre model in which a high-fat diet caused livers so fatty they pushed into the chest; resveratrol rescued those mice, at doses equivalent to drinking your body weight in wine. When the NIA-funded Interventions Testing Program, which runs every experiment in genetically diverse mice at three independent labs, tested resveratrol at doses recommended by the original researchers, it did nothing. The ITP has tested over 50 molecules, and few have worked: rapamycin, even when started in very old mice; the SGLT2 inhibitor canagliflozin; acarbose, which blocks glucose absorption; and 17-alpha estradiol in males only. Notably, acarbose and canagliflozin worked without reducing body weight, suggesting tight glucose control itself matters. Metformin failed, and so did NR, which showed no lifespan or healthspan benefit even at very high doses.

NAD, NADH and the Leaps of Faith

Attia walks through how the body turns food into ATP: chemical energy in carbon bonds is converted into an electrical gradient across the mitochondrial electron transport chain, with NAD and NADH passing electrons, and finally stored again as ATP. A 2015 PNAS study found NAD in blood falls 10 to 20% over four decades while NADH rises by about the same amount, suggesting the real change with age is a decline in redox potential and mitochondrial function rather than a shortage of NAD. Skin shows the largest drop, about 60%, compared with 15 to 20% in the brain. Huberman mentions Glen Jeffery's work at University College London on red and near-infrared light improving photoreceptor function in people over 40, possibly by reducing reactive oxygen species.

Attia then lays out the chain of assumptions behind NAD supplementation: that sirtuins matter, that they relate to caloric restriction (they do not), that yeast findings apply to humans, that sirtuin activators work, and finally that raising NAD in a tightly regulated system will help at all. "It's okay to take leaps of faith. You just have to know you're taking a leap of faith." He invokes a paraphrase of JFK: "people enjoy the comfort of opinion without the discomfort of thought."

NR, NMN and IV NAD in Practice

Huberman shares his own experience. He has had IV NAD infusions five or six times and describes the first ten minutes as feeling like a boot on his chest, with cramping and nausea, followed by feeling good afterward, though saline drips also make him feel good. Attia notes that many people assume the discomfort proves it works: "The fact that something feels so awful shouldn't be used as an explanation for why it's doing good physiologically." Huberman takes 1.5 grams of sublingual NMN in the morning, which he says speeds hair and nail growth and gives him some energy, and sometimes NR, while noting mouse studies use 500 to 1,000 milligrams per kilogram. NR crosses cell membranes directly, while NMN must lose a phosphate group first, but Attia considers the NR versus NMN fight a commercial debate, since doses can simply be adjusted, and says work by Josh Rabinowitz suggests supplemented NAD mostly reaches the blood and liver. IV NAD costs roughly $300 to $1,000 per drip; asked what two hours of exercise would do instead, Attia says the benefit would be significantly greater.

On human trials, Attia describes a roughly 100-person study of NR plus pterostilbene in fatty liver disease that found no difference in liver fat, weight, inflammation or glucose; only a subgroup analysis showed a drop from 20% to 15% liver fat in the low-dose arm, still three times above the fatty liver threshold. A WashU study found NMN slightly improved insulin-stimulated glucose disposal, statistically but not clinically meaningful. "Never confuse statistical significance with clinical significance," he says, adding that "if you have to resort to really interesting statistical machinations to see something, there probably isn't something very interesting there." The one signal he finds genuine is a study showing a 60 to 80% reduction in basal and squamous cell carcinomas, though not melanoma, which he wonders may relate to skin's large NAD decline and which could matter for people with heavy sun exposure. On regulation, NR has generally recognized as safe status, while the FDA has said NMN should not be sold as a supplement because a clinical trial made it an investigational drug, a move Huberman compares to the earlier NAC situation; NMN is still widely sold. Attia believes both are probably safe. His verdict on lifespan: "The answer appears to be unambiguously no at this point."

Biological Age Tests and Radiation

Attia recounts a fancy motion-capture movement test that declared him 22 years old: "There is so much nonsense in this type of testing." The gold standard for any biological age test, he argues, is whether it predicts remaining years of life better than chronological age, and no one believes a 49-year-old testing as 25 has 60 more years ahead. The inputs, from glucose to vitamin D to epigenetic markers, are noisy, and to his knowledge companies were not properly sequencing the epigenome as of about a year earlier. He does see directional value and expects epigenetic measures to improve.

On radiation, he does not worry about airport scanners or flights. For context, living at sea level gives about 1 millisievert a year, Colorado about 2, and a chest CT angiogram 3 to 15, against a recommended annual limit of 50. A DEXA scan is less than a cross-country flight. He has been told nuclear plant workers can receive ten times the limit without increased cancer risk, and knows of no convincing data showing higher cancer rates in pilots who fly polar routes.

The Critical Decades, Energy and Workout Timing

Huberman describes tracking his subjective vigor on a life-in-weeks chart and expecting to work harder in his 80s and 90s to maintain it. Attia argues the decisive window is the 50s through the 70s, when aging starts to show and we must build as much physiological reserve as possible while we can still add muscle. Power declines first, then strength, then muscle size, and his own vertical jump is half what it was as a teenager. The key is to stay in the game and avoid injuries, because at this age each period of inactivity takes two to three times as long to recover from.

On why energy declines with age, a question their late friend Ben Barres used to ask, neither has an answer, and Attia marvels at his young sons sprinting back and forth through a mall. He cannot imagine any supplement or drug, rapamycin included, rivaling sleep, exercise and nutrition for energy, while admitting all three are hard for busy adults. Huberman shares his untested observation that working out before 9 a.m. gives him more energy all day, while mid-morning workouts leave him drained, possibly because of body temperature rhythms; he notes friends like Jocko Willink and Eddie Chang are early exercisers, while Attia raises the possibility of reverse causality.

Their Supplement Routines and the Titanic Analogy

Attia takes EPA and DHA fish oil capsules, Theracurmin based on reasonable evidence for cognitive function in mild cognitive impairment, 5,000 IU of vitamin D, methylfolate and methyl B12 to lower homocysteine (but not B6, which can cause nerve damage), magnesium L-threonate and ashwagandha for sleep plus Slow-Mag and magnesium oxide, LMNT electrolytes (he discloses he is an investor), 5 grams of creatine, AG1, and three Pendulum products including Akkermansia, which he says is the only probiotic he knows of with a meaningful effect. Huberman takes AG1, liquid fish oil for over 1 gram of EPA, vitamin D3, methyl B12, Tongkat Ali, green tea extract, NMN and sometimes NR, LMNT, 10 grams of creatine, magnesium threonate, apigenin and theanine before bed, occasionally inositol, and whey protein, and he recently stopped nicotine gum. Both stress that behaviors like sleep, exercise, nutrition and sunlight matter far more than any supplement.

Attia puts it most vividly: supplements are like asking whether the Titanic was serving lobster or steak, while exercise, sleep, nutrition and emotional health determine where the ship was heading relative to the iceberg. Asked whether to supplement the NAD pathway for longevity, both say no. Attia, invoking the idea of showing what is in your portfolio, says he does not take NR, NMN or NAD: "I passionately do not believe they do anything for me." But he adds, "I will reserve the right to change my mind for the rest of my life in the presence of new data."

Conclusion

This episode is a masterclass in evaluating longevity claims. Peter Attia shows how a compelling mechanistic story, from sirtuins in yeast to declining NAD in aging tissues, can rest on a series of unproven leaps, and how rigorous tools like the Interventions Testing Program, which found no benefit for NR or resveratrol, cut through marketing. Rapamycin, glucose-lowering drugs and caloric restriction have far stronger evidence, though even rapamycin awaits key results. Biological age tests are noisy, everyday radiation is not worth fearing, and the decades from 50 to 70 are the time to build physical reserve. Andrew Huberman's candor about taking NMN anyway adds a human counterpoint, but both land in the same place: the Titanic's heading, meaning sleep, exercise, nutrition and emotional health, matters far more than what is on the menu.

This is a summary of "Dr Peter Attia Supplements For Longevity Their Efficacy" from Huberman Lab, giving you the GIST so you can decide if you want the REST. Listen to the full episode.